3-amino-2,4,6-triiodobenzoic acid derivatives

ABSTRACT

3-AMINO-2,4,6-TRIIODOBENZOIC ACID DERIVATIVES OF THE FORMULA   IN WHICH A is amino, alkylamino, alkenylamino, dialkylamino, dialkenylamino with alkyl or alkenyl having not more than four carbon atoms, alkoxyalkylamino, containing a total of not more than five carbon atoms, piperidino, morpholino, pyrrolidino and 2-methylpiperidino, R2 is a saturated or unsaturated aliphatic dicarboxylic acid having four to six carbon atoms and R3 is hydrogen, alkyl or alkenyl, both having not more than four carbon atoms, and the physiologically acceptable salts thereof, possessing valuable properties, which make them suitable for Xray diagnosis of the gall-bladder.

United States Patent [191 Obendorf et al.

[ Dec. 10, 1974 3-AMINO-2,4,6-TRIIODOBENZOIC ACID DERIVATIVES [75] Inventors: Werner Obendorf; Irmgard Lindner; Josef Krieger; Ernst Schwarzinger, all of Linz/Donau Austria [73] Assignee: Osterreichische Stickstoffwerke Aktiengesellschaft, Linz/Donau, Austria 221 Filed: July 9, 1968 21 App]. No.: 743,299

[30] Foreign Application Priority Data July 13, l967 Austria 6539/67 July 13, 1967 Austria 6538/67 [52] US. Cl ..260/247.2 A, 260/293.77, 260/3264], 260/518 A, 424/248 [51] Int. Cl. C07d 87/42 [58] Field of Search 260/3263, 247.2 A, 518 A [56] References Cited OTHER PUBLICATIONS Chemical Abstracts, Vol. 58, pages 44744475, 1963.

Primary Examiner-Donald G. Daus Assistant Examiner-Jose Tovar Attorney, Agent, or Firm-Wenderoth, Lind & Ponack [5 7] ABSTRACT 3-amino-2,4,6-triiodobenzoic acid derivatives of the formula in which A is amino, alkylamino, alkenylamino, dialkylamino, dialkenylamino with alkyl or alkenyl having not more than four carbon atoms, alkoxyalkylamino v containing a total of not more than five carbon atoms,

5 Claims, No Drawings triiodobenzoic acid derivatives, the preparation therof and X-ray contrast materials containing them.

The present invention provides 3-amino-2,4,6- triiodobenzoic acid derivatives of the general formula in which A is an amino, alkylamino, alkenylamino, dialkylamino or dialkenylamino group, in which the alkyl or alkenyl group contains'not more than fourcarbon atoms, an alkoxyalkylamino group in which the alkoxyalkyl group contains a total of not more than five carbon atoms, or a piperidino, morpholino, pyrrolidino or 2-methylpiperidino residue, R is the residue of a saturated or unsaturated aliphatic dicarboxylic acid having four to six atoms and R is a hydrogen atom or an alkyl- /or alkenyl group having not more than four carbon atoms, as well as the physiologically acceptable salts thereof with inorganic or organic bases.

The compounds of formula I posses valuable properties which make them suitable for X-ray diagnosis purposes. They are capable of being used as the active substance in X-ray contrast materials for rendering visible the gall-bladder and in most cases also the bile ducts. Some of the compounds, preferably those compounds which do not have a free hydrogen atom attached to either the nuclear amino group or the acid amide group,

are particularly suitable for peroral administration, whilst other compounds, namely preferably those compounds which do have free hydrogen atoms attached to the nuclear amino group or the acid amide group or both, are suitable for intravenous administration. On peroral administration of an X-ray contrast material containing a compound of formula I it is noteworthy that the material is particularly rapidly resorbed and its low toxicity makes it favourable as a peroral gallbladder contrast material.

These compounds which are suitable for peroral administration are conspicuous, in animal experiments v with rats, for the high maximum iodine concentration achievable with them; in some cases the mean maximum iodine concentration was 710 to 860 mg .percent,

the maximum concentrations being reached within 60 to 90 minutes after admisistration of the substances. in clinical pharmacological investigations on humans which were for example carried out withthe compound B-[N-(3N,N'-diethyl-carbamyl-2,4,6-triiodophenyl)- N-methyl-carbamyl] propionic acid, an X-ray picture of the gall-bladder could be obtained in 6 out of 10 cases 90 minutes after administration and in 8 out of 10 cases 3 hours after administration, on administering a dose of 50 mg/kg, which was tolerated very well. The compounds according to the invention which are suitable for intravenous administration possess a remarkably low toxicity at iodine concentrations of 850 to 1,000 mg percent in the rat gall-bladder, attainable after intravenous administration. The bile-urine quotient, which can be treated as an expression of the ratio of liver/kidney functioning, was 2 throughout and is 5 thus relatively favourable. The dose to be used in humans is as a rule about 100 mg/kg.

Particularly advantageous active compounds for X-ray contrast materials are compounds of the formulae o OA

| NHC o-cm-cm-C 0 01-1 and dino, morpholino, pyrrolidino or 2'-methylpiperidino 30 residue, as well as compounds of the formulae or their salts, in which formulae each of R and R" is a hydrogen atom, an alkyl group containing not more than four carbon atoms or an alkenyl containing not more than four carbon atoms, with R in all cases being defined as in formula I. A compound to be particularly emphasised is [3-N-(3-N,N'-diethyl1carbamyl-2,4,6 triiodophenyl )-N-methyl-carbamyl+propionic acid.

For peroral administration, the X-ray contrast materials according to the invention may be in the form of tablets, gelatinecapsules or dragees, in admixture with inert fillers and binders such as starch or talc. Aqueous solutions of the salts, for example the sodium salt, the methyl glucamine salt or the diethanolamine salt, are preferably used for intravenous administration.

According to the present invention the compounds of formula I may be prepared by a process which comprises acylating the amino group of a compound having the formula NH (II) in which X is a chlorine atom or the group A, wherein A is as defined for formula I, by reaction with a halide, ester acid halide or anhydride of a dicarboxylic acid of the formula R OH in which R is as defined for formula I, and optionally replacing the second hydrogen atom of the amino group by an alkyl or alkenyl group containing not more than four carbon atoms, by reaction with an appropriate alkyl halide, alkenyl halide or dialkyl sulphate and, in the case in which X in formula ll is a chlorine atom, converting the acid chloride group, after carrying out the acylation reaction and optionally the alkylation re action or between these two reactions, to the corresponding acid amide group by reaction with a compound of the formula in which A is as defined above.

The compound bearing a carboxyl group in the residue R may, if it is produced as such, be subsequently converted to a salt. It is however also possible for salts, or, when starting from ester acid halides of the acids of formula III, esters to be produced as end products and, if desired, these may be converted to the free acids.

The procedure to be recommended for the amidation of the acid chloride group in the l-position of the aromatic nucleus is the one which has become known for the manufacture of amides of 3-amino-2,4,6- triiodobenzoic acid. It is advantageous to work either in an organic solvent such as dioxane, acetone or tetrahydrofurane, or without an organic solvent. In cases where a strong evolution of heat occurs, a controlled reaction must be ensured by cooling. The acylation of the nuclear amino group succeeds best at an elevated temperature in an inert organic solvent, and again dioxane, tetrahdrofurane, chlorobenzene or a mixture of benzene and dimethylformamide are suitable. Any usual alkylation process may be used for introducing the alkyl group into the nuclear amino group, and working in an alkaline medium, i.e., in the presence of a compound which reacts alkaline, such as a caustic alkali, for example caustic soda, caustic potash or an aqueous alkali metal carbonate proves best.

On substitution of the nuclear amino group care must be taken to avoid a dialkyl substitution where, in cases in which an alkylation is desired in addition to an acylation, the acyl residue R is first introduced and the further hydrogen atom only then replaced by R On the other hand it is immaterial at which point in time the group A is introduced if starting from 3-amino-2,4,6- triiodobenzoyl chloride. The amide grouping can only be produced either after complete substitution of the nuclear amino group has been effected, or alternatively the amidation of the acid chloride can be interpolated between the acylating and alkylation of the nuclear amino group.

The 3-amino-3,4,6triiodobenzoyl chloride which serves as the starting material may be prepared accord ing to the process disclosed in US. Pat. No. 3,051,745 of one of the inventors by reacting 3-amino-2,4,6- triiodobenzoic acid with thionyl chloride. preferably in an inert organic medium. The amide of the 3-amino- 2,4,6-triiodobenzoic acid of formula ll are obtained according to the process disclosed in U.S. Pat. No. 3,051,745 by reaction of the acid chloride with an appropriate amine.

Alkaline saponification. for example with an aqueous or alcoholic alkali hydroxide solution, is chosen for the saponification of the ester which is produced in the process according to the invention, whereby as a rule the mixture is heated for a short time. The alkali salt can either be obtained directly from the alkaline saponification solution, for example by precipitiation with an organic solvent, or alternatively the solution is acidified and the compound of formula I is isolated as the free acid. Both acids and salts can be converted into one another. The compounds of formula I exist in part in two geometrically isomeric forms the separation of which is in prinicple possible.

The process according to the invention is illustrated in the following Examples.

Example 1 533.3 of 3-amino-2,4,6-triiodobenzoyl chloride is dissolved in 2200 ml. of chloroform and l65.6 g. of succinic acid monomethyl ester chloride is added drop wise over the course of 3 hours at the boil, with stirring and under reflux. After completion of the HClevolution a total of 585 g. of 3-N (B-carbomethoxypropionyl)-amino-2,4,6-triiodobenzoyl chloride of melting point 184 to 187C, that is to say 904% of theory, crystallises out on concentrating the reaction solution.

585 g. of this ester acid chloride is suspended in 4800 ml. of acetone and reacted with g. of diethylamine. Transient solution occurs, and then B-[N-(3-N,N'- diethylcarbamyl-2,4,6-triiodophenyl )-carbamyl propionic acid methyl ester soon crystallises out. After treatment with boiling water 561 g. of pure substance of melting point 169 to 171C. is obtained, corresponding to a yield of 90.7 percent of theory.

Example 2 68.4 g. of B-lN-(3-N'-N'-diethylcarbamyl-2,4,6- triiodo-phenyl)-carbamyl ]-propionic acid methyl ester, prepared as described in Example I, is reacted, in 500 ml. of dioxane, with a mixture of 12.6 g. of dimethyl sulphate, 50 ml. of 4 N NaOH and 50 ml. of saturated NaCl solution at 10C., whilst stirring. The dioxane crystallises at 5C. and is separated from the aqueous phase. 14.8 g. of largely unmethylated B-[N-( 3-N',N- diethylcarbamyl-2 ,4,6-triiodophe nyl )-carbamyl propionic acid is obtained in the aqueous phase by means of dilute hydrochloric acid. The dioxane, after drying and concentration in vacuo, yields 53 g. of oily B-[N-( 3-N' ,N'-diethylcarbamyl-2,4,6-triiodophenyl N-methylcarbamyl]-propionic acid methyl ester, which can be crystallised from methanol, with an isomer mixture of melting point l3l to 139C. being produced.

If one wishes to isolate the individual isomers it is necessary to proceed as follows:

370 g. of B-[N-(3-N,N'-diethylcarbamyl-2,4,6- triiodophenyl)-carbamyll-propionic acid methyl ester,

prepared as described in Example 1, is saponified to the corresponding acid by warming the solution in 100 g. of caustic soda and 1,500 ml. of water to 75C. The resulting solution is cooled and dimethyl sulphate is added in portions to produce N-methylation. In total, 102.1 g. of dimethyl sulphate are added and the progress of the methylation is followed by thin layer chromatography.

The methylation is complete after about 40 hours. After filtration the mixture is acidified and the precipitate dissolved in 800 ml. of ethyl acetate, and the solution dried, concentrated and cooled to produce crystallisation. 206.9 g. of a chromatographically homogeneous form (of) B-[N-(3-N',N-diethylcarbamyl-2,4,6- triiodophenyl)-N-methylcarbamyl]-propionic acid crystallises out.

Analysis:

calculated: C2809 H 2.8 I 55.66 N 4.10 O 9.36 found: C 28.0 H 2.8 I 55.3 N 4.1 O 9.6

The residue from evaporating the mother liquor to dryness is dissolved in 600 ml. of dilute NaOH, cooled to 0C. after filtration with addition of charcoal, and acidified with dilute HCl The precipitate, whilst still moist, is dissolved on 300 ml. of acetone. After cooling and rubbing crystals separate out which after recrystallisation from ethyl acetate yield a further 46.2 g. of the above-mentioned acid of melting point 178 to 184C.

A vacuum evaporation residue is produced from the mother liquor, dissolved in dilute caustic alkali, and a crude acid obtained therefrom by precipitation with dilutehydrochloric acid, which shows two spots in the thin layer chromatogram. This product, dissolved in 120 ml. of ethyl acetate, overnight deposits 52 g. of crystals of the acid having a melting point of 180 to 184C., which are homogeneous in the chromatogram but show a different R, value from the first crystals. Analysis:

calculated: C 28.09 H 2.80 I 55.66 N 4.10 O 9.36

found: C 28.3 H 2.8 I 55.5 N 4.1 O 9.9

The ethyl acetate mother liquor is evaporated to give a residue, and by dissolving in caustic alkali and precipitation with acid, as already described above, an amorphous product (39.1 g.) is obtained which in the chromatogram shows both isomeric forms. NMR and IR spectra indicate the probability of a structural isomerism in which the acid amide bond participates.

Example 3 12.95 g. of 3-N-(B-carbomethoxypropionyl)-amino- 2,4,6-triiodobenzoyl chloride, prepared as described in Example 1, is dissolved in 100 ml. of dioxane and after addition of 5.1 g. of dimethyl sulphate the solution is treated with 25 ml. of 4 N NaOH at a temperature of C. over the course of minutes. After 15 minutes stirring at room temperature the emulsion is poured into 300 ml. of ether. 11 g. of 3-N-(B-carbomethoxypropionyl)-3-N-methylamino-2,4,6-triiodobenzoyl chloride crystallises out from the dried ether solution.

Melting point 153 to 155C., corresponding to a yield of 84 percent of theory. It diethyl sulphate is used instead of the dimethyl sulphate, then 3-N-(B- carbomethoxypropionyl)-3-N-ethylamino-2,4,6- triiodobenzoyl chloride of melting point 141 to 143C. is obtained.

25 g. of 3-N-ethyl-3-N-(B-carbomethoxypropionyl)- amino-2,4,6-triiodobenz0yl chloride is dissolved in 100 ml. of dioxane and is boiled for 30 minutes under reflux after addition of 50 ml. of concentrated aqueous ammonia. The vacuum evaporation residue is saponified by taking up in 150 ml. of water and 40 ml. of 4 N NaOH and by boiling for about 10 minutes. The reaction solution obtained on acidification yields 18 g. of amorphous B-[N-(3-carbamyl-2,4,6-triiodopheny1)-N- ethylcarbamyl]-propionic acid of melting point 131 to 140C., corresponding to 76 percent of theory.

Example 4 Example 5 27.3 g. of B-[N-(3-N,N'-pentamethylenecarbamyl- 2,4,6-triiodophenyl)-carbamyl]-propionic acid of melting point 209 to 213C., prepared in a manner analogous to that described in Example 4, is dissolved in 120 ml. of 1 N NaOH and, whilst being stirred at room temperature, is first treated with 5 g. of allyl bromide in 30 ml. of acetone and after 5 hours with 3 g. of allyl bromide, and stirred for 1 hour. After heating to 50C. for 2 hours and standing overnight, the mixture is diluted with water and acidified with dilute HCl. The amorphous carboxylic acid thus produced is suspended in ethyl acid and crystallises on heating. 27.3 g. of B-[N- (3-N',N'-pentamethylenecarbamyl-2,4,6- triiodophenyl)-N-allylcarbamyl]-propionic acid of melting point 206 to 211C. is obtained, corresponding to. a yield of 94.5 percent of theory. The following compounds may be prepared in a'manner analogous to that described in the preceding Examples:

B-[N(3-carbamyl-2,4,6-triiodophenyl)-carbamyl]- propionic acid, melting point:- 275 to 280C. y-[N-(3- carbamyl-2,4,6-triiodophenyl)-carbamyl]-butyric acid, melting point:- 264 to 270C. y-[N(3-carbamyl-2,4,6- triiodophenyl)-N-ethylcarbamyl]-butyric acid, melting point:- 198 to 201C. B-[N-( 3-carbamyl-2,4,6- triiodophenyl)-carbamyl]-acrylic acid, melting point:-

.308 to 318C. B-[N-(3-N-methylcarbamyl-2,4,6-

triiodophenyl)-N-methylcarbamyl]-propionic acid, melting point:- 161 to 167C. B-[N-(3-N- methylcarbamyl-2,4,6-triiodophenyl)-N-ethylcarbamyl]-propionic acid, melting point 150 to 156C. 'y-[ N-( 3-N-methylcarbamyl-2,4,6-triiodophenyl carbamyll-butyric acid, melting'pointz- 250 to 258C. B-[N-(3-N',N'-dimethylcarbamyl-2,4,6- triiodophenyl)-carbamyl]-propionic acid, melting point:- to C. B-[N-(3-N',N- dimethylcarbamyl-2,4,6-triiodophenyl)-N-ethylcarbamyll-propionic acid, melting point:- 110 to 118C. (amorphous). B- N-( 3-N -ethylcarbamyl-2,4 ,6-

7 triiodophenyl)-carbamyl]-propionic acid, melting point:- 262 to 266C. B-[N-(3-N'-ethy1carbamyl- 2,4,6-triidophenyl)-N-ethylcarbamyl]-propionic acid, melting point:- 179 to 182C. B-[N-(3-N',N'- diethylcarbamyl-2,4,6-triiodophenyl)-N-ethy1carbamyll-propionic acid, melting point:- 210 to 220C. y-[N-(3-N',N-diethylcarbamyl-2,4,6-triiodophenyl)- carbamyl]-butyric acid, melting point:- 105 to 115C. (amorphous). 'y-[N-(3-N',N'-diethylcarbamyl-2,4,6 triiodophenyl)-N-ethylcarbamyl]-butyric acid, melting point:- 102 to 115C. (amorphous). B-[N-(3-N'- a1lylcarbamyl-2,4,6-triiodophenyl )-N-allylcarbamyl propionic acid, melting point:- 198 to 201C. 'y-[N-(3- N'-allylcarbamyl-2,4,6-triiodophenyl )-carbamyl butyric acid, melting point:- 260 to 271C. B-[N-( 3- N' ,N-diallylcarbarnyl-2,4,6-triiod0phenyl )-N-allyl- 'carbamyH-propionic acid, melting point:- 155 to 160C. B-[N-( 3-N'-3 '-methoxy-propy1carbamyl-2 ,4,6- triiodophenyl)-carbamyl]-acrylic acid, melting point:- 299 to 302C. B-[N-(3-N',N'-3'- oxapentamethylenecarbamyl-2,4,6-triiodophenyl)-carbamyl]-pr0pionic acid, melting point:- 224 to 230C. fi-[N-(3-N',N-3'-oxapentamethylenecarbamyl-2,4,6- triiodophenyl )-N-methylcarbamyl -propionic acid, melting point:- 184 to 190C. B-[N-(3-N,N'-3- oxapentamethylenecarbamyl-2,4,6-triiodophenyl)-N- ethylcarbamylI-propionic acid, melting point:- 214 to 218C. B-[N-(3-N,N'-3'- oxapentamethylenecarbamyl-2,4,6-triiodphenyl)-N- allylcarbamyl1-propionic acid, melting point:- 188 to 192C. B-[N-(3-N ,N'-pentamethylenecarbamyl-2,4,6- tn'iodophenyl)-carbamyl]-propi0nic acid, melting point 209 to 213C. B-[N-( 3-N' ,N'- pentamethylenecarbamyl-2,4,6-triiodophenyl)-N- methylcarbamyl]-propionic acid, melting point:- 199 to 203C. ,8-[N-(3-N',N-pentamethylenecarbamy1- 2,4,6-triiodophenyl)-N-ethylcarbamyl]-propionic acid, melting point:- 194 to 198C. B-[N-(3-N,N'-

tetramethylenecarbamyl-2,4,6-trii0dopheny1)-carbamyU-propionic acid, melting point:- 250 to 255C. B-{N-( 3-N',N-tetramethylenecarbamyl-2,4,6- triiodophenyl )-N-methylcarbamyl l-propionic acid melting point:- 209 to 214C. B-[N-(3-N,N'- tetramethylenecarbamyl-2,4,6-triiodophenyl )-N- ethylcarbamyH-propionic acid, melting point:- to C. B-[N-(3-N,N'-tetramethylenecarbamyl2,4,6- triiodophenyl )N-n-propylcarbamyl 1 -propionic acid melting point: 221 to 225C. B-[N-( 3-N,N'- tetramethylenecarbamyl-2,4,6-trii0d0phenyl )-N- allylcarbamyl1-propionic acid, melting point:- 198 to 202C. ,B-[N-(3-N',N'-2'- methylpentamethylenecarbamyl-2 ,4,6-triiodophenyl carbamyl]-propionic acid, melting point:- 245 to 248C.

The above free acids may be converted to the corresponding sodium salts in the usual manner.

What we claim is:

1. A 3-amino-2,4,6-triiodobenzoic acid derivative, namely, B- N-( 3 N ,N '-diethylcarbamyl )-2,4,6- triiodophenyl)-N-methylcarbamyll-propionic acid.

2. A 3-amino-2,4,6-triiodobenzoic acid derivative, namely, ,B-{N-(3-N',N-3'- oxapentamethylenecarbamyl )-2,4,6-trii0dophenyl )-N- allyl-carbamyl]-pr0pionic acid.

3. A 3-amino-2,4,6-trii0dobenzoic acid derivative, namely, B-[N-( 3-N',N-tetramethylenecarbamyl 2,4,6-triiod0phenyl)-N-allyl-carbamyl]-pr0pionic acid.

4. A 3 amin0-2,4,6-trii0dobenzoic acid derivative, namely, B-[N-(3-N',N'-tetramethylenecarbamyl)' 2,4,6-triiodophenyl)-N-methyl-carbamyl]-propi0nic acid.

5. A 3-amin0-2,4,6-triiodobenzoic acid derivative, namely, y-[N-(3-N,N'-diethyl-carbamyl-2,4,6- triiodophenyl)-N-ethylcarbamyl]-butyric acid. 

1. A 3-AMINO-2,4,6-TRIIODODENZOIC ACID DERIVATIVE, NAMELY, B-(N-(3N'',DIETHYLCARBAMYL)-2,4,6-TRIIODOPHENYL)-NMETHYLCARBAMYL)-PROPIONIC ACID.
 2. A 3-amino-2,4,6-triiodobenzoic acid derivative, namely, Beta -(N-(3-N'',N''-3''-oxapentamethylenecarbamyl)-2,4,6-triiodophenyl)-N-allyl -carbamyl)-propionic acid.
 3. A 3-amino-2,4,6-triiodobenzoic acid derivative, namely, Beta -(N-(3-N'',N''-tetramethylenecarbamyl)-2,4,6-triiodophenyl)-N-allyl-carbamyl) -propionic acid.
 4. A 3-amino-2,4,6-triiodobenzoic acid derivative, namely, Beta -(N-(3-N'',N''-tetramethylenecarbamyl)-2,4,6-triiodophenyl)-N-methyl-carbamyl)-propionic acid.
 5. A 3-amino-2,4,6-triiodobenzoic acid derivative, namely, gamma -(N-(3-N'',N''-diethyl-carbamyl-2,4,6-triiodophenyl)-N-ethylcarbamyl)-butyric acid. 